Removal of methadone by extended dialysis using a high cut-off dialyzer: implications for the treatment of overdose and for pain management in patients undergoing light chain removal.

The synthetic opioid methadone hydrochloride has a low molecular weight of 346 D, a high volume of distribution (4 - 7 L/kg), and is lipophilic. It is used as an analgesic and for the maintenance treatment of opiate dependence. In drug addicts, methadone is frequently involved in mixed intoxications that can lead to death. Here we present the case of a drug addict in whom a high cut-off dialysis membrane together with extended dialysis was used in the setting of suspected overdose and acute kidney injury. Although the observed dialyzer plasma clearance (31.5 mL/min) and reduction ratio (38%) were higher than previously reported for standard hemodialysis, the total amount of methadone in the spent dialysate after 1 extended dialysis session was quite low. Hence, even extended dialysis with a high cut-off membrane does not seem to offer a clinically relevant benefit in the setting of overdose for enhanced methadone removal. On the other hand, in patients undergoing high cut-off dialysis for the removal of light chains, methadone could still be used as an analgesic without an additional dose after high cut-off hemodialysis.

Role of catecholamines in maternal-fetal stress transfer in sheep.

OBJECTIVE: We sought to evaluate whether in addition to cortisol, catecholamines also transfer psychosocial stress indirectly to the fetus by decreasing uterine blood flow (UBF) and increasing fetal anaerobic metabolism and stress hormones. STUDY DESIGN: Seven pregnant sheep chronically instrumented with uterine ultrasound flow probes and catheters at 0.77 gestation underwent 2 hours of psychosocial stress by isolation. We used adrenergic blockade with labetalol to examine whether decreased UBF is catecholamine mediated and to determine to what extent stress transfer from mother to fetus is catecholamine dependent. RESULTS: Stress induced transient increases in maternal cortisol and norepinephrine (NE). Maximum fetal plasma cortisol concentrations were 8.1 ± 2.1% of those in the mother suggesting its maternal origin. In parallel to the maternal NE increase, UBF decreased by maximum 22% for 30 minutes (P < .05). Fetal NE remained elevated for >2 hours accompanied by a prolonged blood pressure increase (P < .05). Fetuses developed a delayed and prolonged shift toward anaerobic metabolism in the presence of an unaltered oxygen supply. Adrenergic blockade prevented the stress-induced UBF decrease and, consequently, the fetal NE and blood pressure increase and the shift toward anaerobic metabolism. CONCLUSION: We conclude that catecholamine-induced decrease of UBF is a mechanism of maternal-fetal stress transfer. It may explain the influence of maternal stress on fetal development and on programming of adverse health outcomes in later life especially during early pregnancy when fetal glucocorticoid receptor expression is limited.

Saving two lives with one dialysis treatment.

Hemodialysis is the extracorporeal treatment of choice for various life-threatening intoxications, with the exception of highly protein-bound substances, which are preferably removed by charcoal hemoperfusion. This technique, however, is limited by its availability and its significant side effects. We present a potentially lifethreatening diphenhydramine (DPH) overdose in a stuporous female patient in which high cut-off hemodialysis was used. Timely detoxification resulted in rapid gain of consciousness, allowing the patient to state the existence and location of another poison victim.

Time-dependent decrement of dermal gadolinium deposits and significant improvement of skin symptoms in a patient with nephrogenic systemic fibrosis after temporary renal failure.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) represents a rare fibrosing disorder occurring after administration of gadolinium-containing contrast agents during renal insufficiency. In order to prove the effect of gadolinium elimination on clinical signs, we identified and quantified gadolinium in skin biopsies of a 62-year-old patient with NSF with regard to improving skin lesions after recovery of renal function. METHODS: Gadolinium deposits were visualized and identified in NSF skin biopsies by light microscopy and transmission electron microscopy (EM) and by scanning EM. Inductively coupled plasma-mass spectrometry (ICPMS) was used for quantifying gadolinium concentration. RESULTS: Transmission EM studies revealed electron-dense material in connective matrix around blood vessels and inside lysosomes of histiocytes and fibroblasts. A remarkable reduction of gadolinium deposits was observed in transmission EM and scanning EM and confirmed by ICPMS in follow-up biopsies. After spontaneous recovery of renal function, his skin induration improved notably over the next 2 years. CONCLUSIONS: The reduction of clinical and histomorphological signs of NSF correlated with decreasing gadolinium concentration in skin biopsies within 3 years. Our study suggests a possible pathogenetic mechanism of NSF including a chance for recovery after elimination of gadolinium and reduced histamine liberation by mast cells.

Single-Dose Pharmacokinetics and Total Removal of Cyclophosphamide in a Patient with Acute Kidney Injury Undergoing Intermittent Haemodialysis and Prolonged Intermittent Kidney Replacement Therapy: A Case Report.

The largest study on cyclophosphamide pharmacokinetics in dialysis patients comprises of 6 subjects. In the 2 decades since these data were obtained, dialyser membranes, treatment intensities, and treatment duration have changed considerably making new pharmacokinetic studies desirable. We aimed to readdress the pharmacokinetics of cyclophosphamide in a 74-year-old critically ill male suffering from ANCA-associated vasculitis. Due to an acute-on-chronic kidney injury, he underwent intermittent (IHD) and prolonged intermittent kidney replacement therapy (PIKRT). IHD was started 7 h after end of a cyclophosphamide infusion with a blood/dialysate flow of 300 mL/min for 255 min, followed by PIKRT with a blood/dialysate flow of 140 mL/min for 540 min, both using a 1.3 m2 polysulphone high-flux dialyser (F60S, Fresenius Medical Care). Peak concentration of cyclophosphamide was 20.2 mg/L. Using IHD and PIKRT serum concentration of cyclophosphamide decreased to 1.2 mg/L after IHD and to <0.1 mg/L after PIKRT with dialyser-clearances of 153.0 mL/min and 84.9 mL/min, respectively. Total recovery of cyclophosphamide, calculated from the collected dialysate, was 57.5 mg (7.7% of administered dose) for IHD and was 8.3 mg (1.1% of administered dose) for PIKRT. By using IHD with a high-flux dialyser cyclophosphamide could be eliminated. Remaining cyclophosphamide should be eliminated by PIKRT. Hence, even in the absence of renal function a dose >50% of the recommended for patient with normal renal function may be applied, as complete elimination of the parent drug by modern dialysis is feasible.

Diet and food type affect urinary pesticide residue excretion profiles in healthy individuals: results of a randomized controlled dietary intervention trial.

BACKGROUND: Observational studies have linked pesticide exposure to various diseases, whereas organic food consumption has been associated with positive health outcomes. Organic farming standards prohibit the use of most pesticides, and organic food consumption may therefore reduce pesticide exposure. OBJECTIVES: To determine the effects of diet (Western compared with Mediterranean) and food type (conventional compared with organic) and sex on urinary pesticide residue excretion (UPRE), as well as associations between specific diet components and UPRE. METHODS: In this 2-wk, randomized dietary intervention trial, healthy adults were randomly allocated to an intervention (n = 13) or conventional (n = 14) group. Whereas participants in the intervention group consumed a Mediterranean diet (MedDiet) made entirely from organic foods, the conventional group consumed a MedDiet made entirely from conventional foods. Both groups consumed habitual Western diets made from conventional foods before and after the 2-wk intervention period. The primary outcome was UPRE. In addition, we assessed diet composition and pesticide residue profiles in foods eaten. Participants were aware of group assignment, but the study assessors were not. RESULTS: During the intervention period, total UPRE was 91% lower with organic (mean 17 µg/d; 95% CI: 15, 19) than with conventional (mean 180 µg/d; 95% CI: 153, 208) food consumption (P < 0.0001). In the conventional group, switching from the habitual Western diet to the MedDiet increased insecticide excretion from 7 to 25 µg/d (P < 0.0001), organophosphate excretion from 5 to 19 µg/d (P < 0.0001), and pyrethroid residue excretion from 2.0 to 4.5 µg/d (P < 0.0001). Small but significant effects of sex were detected for chlormequat, herbicide, and total pesticide residue excretion. CONCLUSIONS: Changing from a habitual Western diet to a MedDiet was associated with increased insecticide, organophosphate, and pyrethroid exposure, whereas organic food consumption reduced exposure to all groups of synthetic chemical pesticides. This may explain the positive health outcomes linked to organic food consumption in observational studies. This trial was registered at www.clinicaltrials.gov as NCT03254537.

Nifedipine gastrointestinal therapeutic system (GITS) as an alternative to slow-release for tocolysis--tolerance and pharmacokinetic profile.

OBJECTIVE: To determine nifedipine plasma concentrations after a loading dose of nifedipine 10mg capsules, 40 mg over 1h followed by slow-release tablets (60 mg/d) versus gastrointestinal therapeutic system (GITS) tablets (90 mg/d) for tocolysis. STUDY DESIGN: Prospective study in 14 pregnant women treated for threatened preterm labor. RESULTS: Following capsule administration there was a rapid rise in plasma concentration of drug achieving a peak of 97.5 microg/l (median) at 1h, then declined to 59.5 microg/l (median) at 5h. The concentration measured at 7200 min (120 h) was non-significantly higher in the slow-release group (median 25.5, range 6.9-67.2 microg/l) than in the GITS group (median 14.6, range 6.0-20.0 microg/l). Area under the curve (AUC) increased with the applied dose in both groups in a linear regression. Headache was more frequent in the slow-release group than in the GITS group (P=0.001). CONCLUSIONS: GITS tablets 90 mg/d are an alternative dosage regimen to previous used slow-release tablets 60 mg/d for tocolysis with similar pharmacokinetic profile and a good tolerance. However, tocolysis with GITS tablets is simpler than that with slow-release tablets and may be associated with a higher compliance. GITS tablets are therefore also qualified for home monitoring.

Enhanced elimination of cyclophosphamide by high cut-off haemodialysis: single-dose pharmacokinetics in a patient with cast nephropathy.

High cut-off (HCO) haemodialysis removes free light chains in patients with multiple myeloma. This is possible as HCO dialysers allow clearance of molecules up to a molecular weight of 65 kDa. In contrast, high-flux dialysers, which are used in routine haemodialysis, only remove molecules up to a molecular weight of 20 kDa. Even though patients with advanced myeloma frequently need dialysis and alkylating agents, drug dosing recommendations in this patient population are scarce at best or absent as for cyclophosphamide dosing in patients with myeloma undergoing HCO dialysis. Therefore, we aimed to determine pharmacokinetics of cyclophosphamide in a 52-year-old man (height 172 cm, weight 80 kg) with cast nephropathy. Intermittent 4-hour haemodialysis was started ~6 hours after the end of a 70 min cyclophosphamide infusion containing 1700 mg of this drug. Blood/dialysate flow rates were 300/500 mL/hour, respectively. Peak concentration of cyclophosphamide was 24.7 mg/L. Using HCO dialysis, plasma concentration of cyclophosphamide decreased from 10.8 mg/L to 3.7 mg/L during the treatment. The calculated whole blood dialyser clearance was 166 mL/min. HCO dialysis led to a marked decrease of cyclophosphamide resulting in a a 50% reduction in half-life as compared with the half-life before dialysis. This removal has to be accounted for in dosing cyclophosphamide.

Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder.

Transcription factor NRF2, encoded by NFE2L2, is the master regulator of defense against stress in mammalian cells. Somatic mutations of NFE2L2 leading to NRF2 accumulation promote cell survival and drug resistance in cancer cells. Here we show that the same mutations as inborn de novo mutations cause an early onset multisystem disorder with failure to thrive, immunodeficiency and neurological symptoms. NRF2 accumulation leads to widespread misregulation of gene expression and an imbalance in cytosolic redox balance. The unique combination of white matter lesions, hypohomocysteinaemia and increased G-6-P-dehydrogenase activity will facilitate early diagnosis and therapeutic intervention of this novel disorder.The NRF2 transcription factor regulates the response to stress in mammalian cells. Here, the authors show that activating mutations in NRF2, commonly found in cancer cells, are found in four patients with a multisystem disorder characterized by immunodeficiency and neurological symptoms.

Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction.

Nitric oxide (NO), a potent regulator of myocardial contractility, has been implicated in the development of heart failure; however, no study exists describing the relation between expression of inducible nitric oxide synthase (iNOS), formation of NO in vivo, and cardiac contractility. We have therefore generated transgenic (TG) mice overexpressing iNOS under the cardiospecific alpha-myosin heavy chain (alpha-MHC) promoter. In vitro, iNOS activity in hearts of two transgenic lines was 260- to 400-fold above controls (wild type [WT]), but TG mice were viable and appeared normal. Ventricular mass/body weight ratio did not differ; heart rate and cardiac output as well as mean arterial blood pressure were decreased by 10%. NO(x) levels of hearts and blood of TG mice were 2.5- and 2-fold above WT controls, respectively. In the isolated heart, release of the NO oxidation products nitrate and nitrite, an index of in vivo NOS activity, was 40-fold over WT. However, cardiac hemodynamics and levels of ATP and phosphocreatine were unaltered. The high iNOS activity was associated with reduced cardiac L-arginine in TG hearts to only 15% of the WT, indicating limited substrate availability, whereas L-citrulline was 20-fold elevated. Our findings demonstrate that the heart can tolerate high levels of iNOS activity without detrimental functional consequences. The concept that iNOS-derived NO is the triggering factor in the pathomechanism leading to heart failure therefore needs to be reevaluated.

Sickle cell anemia: conclusions from a forensic case report of a young African woman who died after anesthesia.

A 20-year old African woman underwent anesthesia for interruption of an unwanted pregnancy. As a consequence of the anesthesia, she went into coma because of an as yet unknown and untested homozygotic state of sickle cell anemia. Her vital functions were maintained for more than 1 year by intensive medicine, but she died finally in multiorgan failure and aspiration pneumonia. Because of the complications under anesthesia and the missing preanesthetic test for hemoglobinopathy, autopsy was conducted in the forensic medicine department and not in the department of pathology. The sickle cell disease was diagnosed by electrophoresis of the blood, by molecular detection of mutation in the hemoglobin gene, as well as by postmortem light and electron microscopy. Sickle cells were found in capillaries of brain, liver, lung, bone marrow, and spleen. Electrophoretic analysis revealed 80.2% HbS in addition to 3.2% HbA2 and 16.6% HbF, whereas no HbA0 could be detected in blood, confirming the homozygosity of sickle cell anemia. Because of sickle cell crisis, occluded blood vessels, and severe brain cortex necrosis, the patient died in spite of reanimation and intensive medicine. This case demonstrates that it is still important to realize the possibility of this disease and diagnostic obstacles even in regions where its manifestation is not endemic, as in Northern and Central Europe.

Treatment of amitriptyline intoxications by extended high cut-off dialysis.

Antidepressants, especially amitriptyline, are among the most frequent drug classes involved in intoxications. Despite its small molecular weight, amitriptyline is not considered to be eliminated by extracorporeal treatment methods due to its high protein binding and large volume of distribution. New high cut-off dialysers have so far not been used for removal of amitriptyline. We report two cases of amitriptyline poisoning in which we measured the amitriptyline elimination using extended high cut-off (HCO) dialysis. Despite dialyser clearances of 33 and 58 mL/min, resulting in the reduction of initial serum concentrations by ∼30%, only 211 and 920 µg of amitryptilin, respectively, (<3% of the ingested amount) could be recovered in the total collected dialysate. Hence, due to the high volume of distribution of amitriptyline, even HCO dialysis does not contribute substantially to the extracorporeal removal of amitryptilin.

Cotrimoxazole plasma levels, dialyzer clearance and total removal by extended dialysis in a patient with acute kidney injury: risk of under-dosing using current dosing recommendations.

BACKGROUND: Dosing of antibiotics in critically ill patients is challenging. It becomes even more difficult if renal or hepatic impairment ensue. Modern means of renal replacement therapy are capable of removing antibiotics to a higher rate than decades ago, leaving clinicians with a high degree of uncertainty concerning the dose of antibiotics in this patient population. Cotrimoxazole, a combination of trimethoprim (TMP) and sulfamethoxazole (SMX) is frequently used in the treatment of several infections including Pneumocystis jirovecii pneumonia (PCP). CASE PRESENTATION: Here we describe a patient with acute kidney injury in which we investigated the TMP and SMX levels during the course of an ICU stay. Cotrimoxazole was administered every six hours i.v. in a dose of TMP/SMX 15/75 mg/kg/day. Extended dialysis was performed with a high-flux dialyzer. Blood samples, as well as pre- and postdialyzer samples and aliquots of the collected spent dialysate were collected.Observed peak concentrations (Cmax) were 7.51 mg/l for TMP and 80.80 mg/l for SMX. Decline of blood levels during extended dialysis (TMP 64%; SMX 84%) was mainly due to removal by the dialysis procedure, illustrated by the high dialyzer clearances (median of 4 extended dialysis sessions: TMP 94.0 / SMX 51.0 ml/min), as well as by the absolute amount of both substances in the collected spent dialysate (median of 6 extended dialysis sessions: TMP 556 mg / SMX 130 mg). Within the limitation of a case report our data from 4 consecutive extended dialysis sessions suggest that this procedure substantially removes both TMP and SMX. CONCLUSIONS: Dose reduction, which is usually advocated in patients with acute kidney injury under renal replacement therapy, might lead to significant under-dosing. Pharmacokinetic studies for TMP/SMX dosing in this patient population are necessary to allow adequate dosing.

Tissue concentration of paraquat on day 32 after intoxication and failed bridge to transplantation by extracorporeal membrane oxygenation therapy.

BACKGROUND: Paraquat is a highly toxic herbicide, which not only leads to acute organ damage, but also to pulmonary fibrosis. There are only anecdotal reports of rescue lung transplantation, as paraquat is stored and only slowly released from different tissues. Bridging the time to complete depletion of paraquat from the body could render this exceptional therapy strategy possible, but not much is known on the time interval after which transplantation can safely be performed. CASE PRESENTATION: We report on a case of accidental paraquat poisoning in a 23 years old Caucasian man, who developed respiratory failure due to pulmonary fibrosis. The patient was listed for high urgency lung transplantion, and extracorporeal membrane oxygenation was implemented to bridge the time to transplantation. The patient died 32 days after paraquat ingestion, before a suitable donor organ was found. In postmortem tissue specimen, no paraquat was detectable anymore. CONCLUSION: This case report indicates that complete elimination of paraquat after oral ingestion of a lethal dose is achievable. The determined time frame for this complete elimination might be relevant for patients, in which lung transplantation is considered.

Enhancement of blood glucose lowering effect of a sulfonylurea when coadministered with an ACE inhibitor: results of a glucose-clamp study.

BACKGROUND: To investigate if coadministration of enalapril alters the metabolic effect of glibenclamide by employing an euglycemic glucose-clamp technique in healthy volunteers. METHODS: A double-blind crossover study with nine healthy normotensive volunteers (age 27 +/- 3 y, BMI 23.3 +/- 2.0 kg m(-2); mean +/- SD)-randomly assigned to a 3-day treatment of either 5 mg enalapril or placebo. In the morning of the fourth day, volunteers orally received 3.5 mg glibenclamide together with either 10 mg enalapril or placebo. Blood glucose levels of volunteers were allowed to fall by 10% from fasting levels and were kept constant thereafter by employing a Biostator-based euglycemic glucose clamp. RESULTS: Coadministration of enalapril-compared with placebo-resulted in a temporarily higher metabolic effect of glibenclamide (AUC GIR(0-120)229 +/- 173 vs 137 +/- 44 mg kg(-1), p < 0.01; mean +/- SD), which lasted from 120 min to 240 min after enalapril administration. In parallel, the maximal metabolic effect of glibenclamide tended to be higher with enalapril (GIR(max)5.2 +/- 1.9 vs 4.1 +/- 1.3 mg kg(-1) min(-1); p = 0.19). However, the total metabolic effect of glibenclamide was almost identical between volunteers taking enalapril or placebo (AUC GIR(0-600)1267 +/- 334 vs 1286 +/- 249 mg kg(-1), ns). In contrast, serum insulin levels, C-peptide levels, and serum glibenclamide profiles were not significantly different between enalapril and placebo. CONCLUSIONS: The results of this study may explain the higher incidence of hypoglycemic episodes observed in patients with type 2 diabetes when taking ACE inhibitors together with sulfonylureas or insulin. ACE inhibitors may cause a temporary increase of the insulin sensitivity, which leads to an increased risk of hypoglycemia under these conditions.